Background: Few studies have investigated the relationship between physician and patient-assessed performance status (PS) in blood cancers. Methods: Retrospective analysis among 1418 patients with haematologic malignancies seen at Dana-Farber Cancer Institute between 2007 and 2014. We analysed physician-patient agreement of Eastern Cooperative Oncology Group PS using weighted kappa-statistics and survival analysis. Results: Mean age was 58.6 years and average follow-up was 38 months. Agreement in PS was fair/moderate (weighted kappa = 0.41, 95% CI 0.37-0.44). Physicians assigned a better functional status (lower score) than patients (mean 0.60 vs 0.81), particularly when patients were young and the disease was aggressive. Both scores independently predicted survival, but physician scores were more accurate. Disagreements in score were associated with poorer survival when physicians rated PS better than patients, and were modified by age, sex and severity of disease. Conclusions: Physician-patient disagreements in PS score are common and have prognostic significance.

Células T de memória são a marca registrada da imunidade adaptativa, e podem ser caracterizadas em central memory (TCM) e effector memory (TEM) T cells. A participação destas células no curso de doenças hematológicas é descrita como mecanismo relacionado à evolução das mesmas. Neste trabalho, analisamos o sangue periférico de doadores de sangue e pacientes com Mielodisplasia (SMD), Mieloma Múltiplo (MM) e Leucemia linfocítica crônica B (LLC), e avaliamos a distribuição das células T CD4+ e CD8+ naive e de memória. SMD e MM não apresentaram resultados significativos, mas na LLC, as células T CD4+ estavam alteradas e dependentes do prognóstico, com aumento das células TCM somente nos pacientes com prognóstico ruim. Essas evidências sugerem que interações imunológicas entre células B da LLC e células T CD4+ possa ser um mecanismo próprio da doença que venha interferir na fisiopatologia e favorecer a geração de células TCM, que podem fornecer sinais de sobrevivência, como citocinas e CD40L, contribuindo assim para o estabelecimento e agressividade da LLC. / Memory T cells are the hallmark of adaptive immunity and are characterized as central (TCM) and effector memory (TEM) T cells. The influence of T cells in the course of hematological malignancies has been described as a mechanism related to the evolution. In this study, we analyzed the peripheral blood of healthy donors and patients with myelodysplastic syndrome (MDS), multiple myeloma (MM) and chronic lymphocytic leukemia B (CLL), and analyzed the distribution of CD4+ and CD8+ naive and memory T cells. MDS and MM revealed no significant difference, but CLL patients showed changes in CD4+ T cell and it were dependent on the prognosis. Patients with poor prognosis presented increased in frequency and absolute number of TCM cells. These evidences show that immunological interactions between CLL and CD4+ T cells could be a disease mechanism that could interfere in pathophysiology and result in the generation of TCM cells, that provide survival signals to the tumor clone, such as cytokines and CD40L, thus contributing to establishment and more aggressive CLL progression.

The aim of this thesis was to determine the relevant dose of arbepoetin-alfa (DA) in patients with lymphoproliferative diseases (LPD) and chemotherapy induced anemia (CIA), to study the clinical impact of intravenous (IV) iron supplementation combined with epoetin beta treatment, to identify factors that might predict hemoglobin (Hb) response to treatment with epoetins and to investigate safety of DA. A dose-finding phase II study was able to assess a reasonable DA dose of 2.25 μg/kg once weekly for the treatment of CIA in patients with LPD. Dose-response trends were observed for the different dose cohorts although not statistically significant for any of the endpoints. However a significantly higher proportion of patients achieved Hb response (increase ≥2 g/dL) in the combined DA groups than in placebo (P<0.001). A larger pivotal phase II trial was performed in a similar setting o confirm that the dose 2.25μg/kg once weekly was appropriate and safe. The proportion of patients achieving Hb response was significantly higher in the DA group (60%) than in the placebo group (18%) (P<0,001) and resulted in higher mean changes in Hb than placebo from baseline, 2.66 g/dl versus 0.69 /dl. Also a significantly lower proportion of patients in the DA group (31%) received RBC tranfusions than in the placebo group (48%). The short-term safety of DA with the tested dose was confirmed. The efficacy of DA was consistent for all end points independent of malignancy type or baseline endogenous erythropoietin serum levels. The correction of moderate anemia in truly iron repleted patients with clinically stable LPD not receiving hemotherapy or RBC transfusions with epoetin beta treatment, with or without IV iron treatment was studied in an open label randomized trial. Also the impact on iron kinetics was assessed. The mean change in Hb concentration from baseline to end of treatment (EOT ) was 2.91 versus 1.50 g/dL respectively (P<0.0001). There was a significant (P<0.0001) difference in mean Hb at EOT between the iron and no-iron groups (13.0 g/dL versus 11.8 g/dL). Hb response was achieved by significantly more patients in the iron group (P=0.0012)than in the no-iron group (93% versus 53%) and the median time to achieve a Hb response was 6 weeks in the iron group compared with 12 weeks in the no-iron group. The mean weekly epoetin dose per patient was statistically significant lower in the iron group at week 13 (P =0.029) and at least 25% lower at EOT. To investigate the long-term safety of DA in cancer patients with CIA four previously published double blind, randomized placebo-controlled phase II -III studies were analysed (n = 1.129). Median durations of progression-free survival and overall survival was comparable between DA and placebo for lung cancer (median follow up 15.8 months), for LPD (median follow up 32.6 months) and in the pooled population (follow up 4 months).

Tidigare studier har fokuserat på barn och deras familjers upplevelser i samband med en hematologisk malignitet, framförallt leukemi. Hematologiska maligniteter är ett samlingsnamn för leukemi och några andra blodsjukdomar. Prevalensen för sjukdomarna ökar och främst vuxna drabbas. Syftet med studien var att beskriva patienters upplevelser av att leva med en hematologisk malignitet. Metoden för denna litteraturöversikt var kvalitativ. Fem artiklar och två avhandlingar analyserades. Studiens resultat utvecklades till fyra huvudteman: att få en sjukdom, att genomgå behandling, upplevelse av vårdmöten och att skakas om i sin livsvärld. Resultatet visar att sjukdomen upplevs som ett osynligt hot och att det ibland förekommer ett vårdlidande som beror på bristfälligt engagemang för människan bakom den sjuka kroppen. Att genomgå en svår tid med lidandets olika aspekter, förändrade oftast människors syn på sig själva och sina medmänniskor. Relationer fördjupades. Förbättringar i omvårdnadsarbetet kan göras genom ökad fokus på patienters känslomässiga lidande då studien visar att denna aspekt ibland förbises och detta resulterar i en objektifiering av patienter. / Previous studies have focused on children and their families' experiences in connection with a haematological malignancy, especially leukemia. Hematolocical malignancies is a collective name for leukemia and other blood diseases. The prevalence of diseases is increasing and affects mainly adults. The purpose of this study is to describe patients' experiences of living with a haematological malignancy. The methodology for this literature review was qualitative. Five articles and two dissertations were analyzed. Results of the study, developed into four main themes: to get a disease, to undergo treatment, experience of care meetings and to shake in their life-world. The result shows that the disease is perceived as an invisible threat, and that sometimes there is a health suffering due to inadequate involvement of the person behind the disease body. To undergo a difficult time with various aspects of suffering often alters people's views of themselves and their fellow human beings and relationships deepen. Improvements in care work can be done by increasing the focus on patients' emotional distress when the study shows that this aspect is sometimes overlooked and it results in an objectification of patients.

<p>Tidigare studier har fokuserat på barn och deras familjers upplevelser i samband med en hematologisk malignitet, framförallt leukemi. Hematologiska maligniteter är ett samlingsnamn för leukemi och några andra blodsjukdomar. Prevalensen för sjukdomarna ökar och främst vuxna drabbas. Syftet med studien var att beskriva patienters upplevelser av att leva med en hematologisk malignitet. Metoden för denna litteraturöversikt var kvalitativ. Fem artiklar och två avhandlingar analyserades. Studiens resultat utvecklades till fyra huvudteman:</p><p>att få en sjukdom, att genomgå behandling, upplevelse av vårdmöten och att skakas om i sin livsvärld. Resultatet visar att sjukdomen upplevs som ett osynligt hot och att det ibland förekommer ett vårdlidande som beror på bristfälligt engagemang för människan bakom den sjuka kroppen. Att genomgå en svår tid med lidandets olika aspekter, förändrade oftast människors syn på sig själva och sina medmänniskor. Relationer fördjupades. Förbättringar i omvårdnadsarbetet kan göras genom ökad fokus på patienters känslomässiga lidande då studien visar att denna aspekt ibland förbises och detta resulterar i en objektifiering av patienter.</p> / <p>Previous studies have focused on children and their families' experiences in connection with a haematological malignancy, especially leukemia. Hematolocical malignancies is a collective name for leukemia and other blood diseases. The prevalence of diseases is increasing and affects mainly adults. The purpose of this study is to describe patients' experiences of living with a haematological malignancy. The methodology for this literature review was qualitative. Five articles and two dissertations were analyzed. Results of the study, developed into four main themes:</p><p>to get a disease, to undergo treatment, experience of care meetings and to shake in their life-world. The result shows that the disease is perceived as an invisible threat, and that sometimes there is a health suffering due to inadequate involvement of the person behind the disease body. To undergo a difficult time with various aspects of suffering often alters people's views of themselves and their fellow human beings and relationships deepen. Improvements in care work can be done by increasing the focus on patients' emotional distress when the study shows that this aspect is sometimes overlooked and it results in an objectification of patients.</p>

alpha-TEA (alpha-tocopherol ether linked acetic acid) has been shown to induce apoptosis in human prostate, ovarian and breast cancer cells in culture and in xenograft models by promoting pro-apoptotic pathways and inhibiting anti-apoptotic pathways. Studies investigated the ability of alpha-TEA to induce apoptosis in human hematological malignant cell lines Jurkat, Raji and U266, representing T cell leukemia, B cell lymphoma and multiple myeloma, respectively. The three cell lines were cultured in the presence of different concentrations of alpha-TEA for different time periods, and examined for apoptosis by annexin V – FITC analyses, DAPI staining, and western blotting for poly (ADP-ribose) polymerase cleavage. alpha-TEA induced apoptosis in all three cell lines in a dose and time dependent manner. Levels of pro-apoptotic molecules DR5, c-Jun N-terminal protein kinase (JNK), C/EBP homologous protein (CHOP), caspase 9, and caspase 3 were upregulated in alpha-TEA treated cells in comparison to vehicle controls. Caspase 8 was activated in Jurkat and U266 cells but not in Raji cells. Apoptosis and pro-death signaling mediators were blocked by ceramide inhibitor, desipramine. The anti-apoptotic nuclear factor kappa B (NF-[kappa]B) signaling pathway was down-regulated in alpha-TEA treated Raji and U266 cells. Combinations of omega-3 fatty acid docosahexaenoic (DHA) and alpha-TEA significantly enhanced apoptosis in Jurkat cells in comparison to single treatments and vehicle control. In summary, alpha-TEA induced apoptosis in the malignant hematological cell lines is via shared and distinct pathways. ASMase/ceramide-mediated JNK activation and endoplasmic reticulum (ER) stress mitochondrial dependent apoptosis are involved in alpha-TEA induced apoptosis in the three cell lines; however, the cell lines exhibit cell type-specific responses to alpha-TEA: activation of death receptor/caspase 8 pathway is involved in Jurkat cells, suppression of NF-[kappa]B signaling is involved in Raji cells, and the U266 cells share both of these pathways for the induction of apoptosis. / text

Células T de memória são a marca registrada da imunidade adaptativa, e podem ser caracterizadas em central memory (TCM) e effector memory (TEM) T cells. A participação destas células no curso de doenças hematológicas é descrita como mecanismo relacionado à evolução das mesmas. Neste trabalho, analisamos o sangue periférico de doadores de sangue e pacientes com Mielodisplasia (SMD), Mieloma Múltiplo (MM) e Leucemia linfocítica crônica B (LLC), e avaliamos a distribuição das células T CD4+ e CD8+ naive e de memória. SMD e MM não apresentaram resultados significativos, mas na LLC, as células T CD4+ estavam alteradas e dependentes do prognóstico, com aumento das células TCM somente nos pacientes com prognóstico ruim. Essas evidências sugerem que interações imunológicas entre células B da LLC e células T CD4+ possa ser um mecanismo próprio da doença que venha interferir na fisiopatologia e favorecer a geração de células TCM, que podem fornecer sinais de sobrevivência, como citocinas e CD40L, contribuindo assim para o estabelecimento e agressividade da LLC. / Memory T cells are the hallmark of adaptive immunity and are characterized as central (TCM) and effector memory (TEM) T cells. The influence of T cells in the course of hematological malignancies has been described as a mechanism related to the evolution. In this study, we analyzed the peripheral blood of healthy donors and patients with myelodysplastic syndrome (MDS), multiple myeloma (MM) and chronic lymphocytic leukemia B (CLL), and analyzed the distribution of CD4+ and CD8+ naive and memory T cells. MDS and MM revealed no significant difference, but CLL patients showed changes in CD4+ T cell and it were dependent on the prognosis. Patients with poor prognosis presented increased in frequency and absolute number of TCM cells. These evidences show that immunological interactions between CLL and CD4+ T cells could be a disease mechanism that could interfere in pathophysiology and result in the generation of TCM cells, that provide survival signals to the tumor clone, such as cytokines and CD40L, thus contributing to establishment and more aggressive CLL progression.

The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a critical role in the cellular response to stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan. We hypothesized that the FA/BRCA DNA damage repair pathway mediates response and resistance to chemotherapeutic agents used to treat multiple myeloma and other cancers, and targeting this pathway is vital to overcoming drug resistance. In this dissertation, we show that FA/BRCA pathway genes are collectively overexpressed in MM, prostate, and ovarian cancer cell lines selected for resistance to melphalan and cisplatin, respectively. Interestingly, cells selected for resistance to topoisomerase II inhibitors selectively overexpress only FANCF. We also show that FA/BRCA pathway expression can be inhibited by the proteasome inhibitor bortezomib. FA/BRCA pathway mRNA expression was inhibited by bortezomib in myeloma cell lines and patient samples. FANCD2 gene and protein expression are downregulated by bortezomib, and remain attenuated in the face of melphalan treatment. Melphalan-induced FANCD2 foci formation was also inhibited by bortezomib, and this drug enhanced melphalan-induced DNA damage, likely via inhibition of FA-mediated DNA damage repair. Next, we analyzed regulation of the FA/BRCA pathway. We demonstrate that NF-kappaB, specifically the Re1B/p50 subunits, transcriptionally regulates members of the FA/BRCA pathway, and inhibition of these subunits by siRNA, BMS-345541, and bortezomib reduces FA/BRCA pathway expression. Furthermore, knocking down Re1B and p50 simultaneously attenuates FANCD2 protein expression and results in diminished DNA repair and enhanced sensitivity to melphalan. Importantly, melphalan resistance was restored when FANCD2 was re-expressed in these cells. We also show that bortezomib regulates FANCD2 protein expression directly, by inhibiting FANCD2 synthesis. Finally, we demonstrate that low-dose bortezomib arrests cells in G0/G1 and also overcomes the S-phase arrest induced by melphalan, likely via inhibition of ATR. Overall, our findings provide evidence for targeting the FA/BRCA pathway, either directly or indirectly, via inhibition of NF-kappaB or ATR, to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma and other cancers.

Haematological malignancies and their treatment lead to prolonged periods of severe thrombocytopenia (platelet count ≤ 50 x 10⁹/l). Despite the use of prophylactic platelet transfusions, haemorrhage remains an important complication during this thrombocytopenic period. Within a 30 day period up to 70% of patients have clinically significant haemorrhage (World Health Organization (WHO) grade 2 or above bleeding) and up to 10% have severe or life-threatening haemorrhage (WHO grade 3 or 4 bleeding). Hence our current management of these patients to prevent haemorrhage is sub-optimal. The aim of this thesis was to identify clinical and laboratory factors that may predict the risk of haemorrhage in patients with haematological malignancies and severe thrombocytopenia. This was achieved via several different study designs and assessed the effect of clinical and laboratory factors on any or clinically significant haemorrhage and their effect on intracranial haemorrhage. This thesis has demonstrated that there is no consensus on how bleeding is assessed and graded in this patient group. Also it showed that the absolute immature platelet number may be a better alternative to the total platelet count to guide administration of platelet transfusions. Female sex, a previous history of a fungal infection, a high C-reactive protein, a high white cell count, a low platelet count, anaemia, impaired renal function, and recent clinically significant haemorrhage were all found to be independent risk factors for haemorrhage. Patients who were in complete remission from their haematological malignancy had a much lower risk of bleeding.

<p>Malignant tumours of the small intestine are rare. Age-standardised incidence in Europe is between 0.5-1.5 per 100 000. As the small intestine represents more than 90 % of the gastrointestinal mucosal surface, it is surprising that it gives rise to less than 2 % of gastrointestinal malignancies. The dominating histological subtypes are carcinoids and adenocarcinomas. </p><p>We used three population-based registries in Sweden to study survival, second malignant tumours, causes of death, and Crohn’s disease as a risk factor for small intestinal adenocarcinoma and carcinoid.</p><p>We evaluated tumour site, sex, age, and year of diagnosis as prognostic factors. For adenocarcinomas there was no difference in survival between duodenal and jejunal/ileal tumours. Women with jejunal/ileal adenocarcinomas showed higher probabilities of survival than men, while no such relation was found for duodenal tumours. Old age correlated with poor survival for duodenal tumours, and prognosis has improved in later years. For carcinoids, duodenal tumours had a more favourable prognosis than jejunal/ileal tumours. There was no difference in survival between sexes. Old age correlated with poor survival, and survival has improved in recent years.</p><p>Female patients with adenocarcinoma had increased risk of acquiring cancer in the genital organs and breasts, and both sexes had increased risks of second tumours in the gastrointestinal tract and skin. Men with carcinoid tumours had increased risk of prostate cancer. Both sexes had increased risk of malignant melanoma and malignancies of endocrine organs.</p><p>Patients with adenocarcinoma had increased risk of dying from malignant diseases other than the primary small intestinal cancer and from gastrointestinal disease. The cohort with carcinoid had higher than expected risk of dying from malignant disease, gastrointestinal disease, and cardiovascular disease.</p><p>Patients with Crohn’s disease had increased risk of small intestinal adenocarcinoma and carcinoid, and the risk has increased for patients diagnosed in recent years.</p>